The central questions of this report were concerned with testing widely held theories concerning the mechanisms regulating the acid-base status of cerebrospinal fluid (CSF) and the role of this acid-base status as a mediator of ventilatory acclimatization to chronic hypobaric hypoxia (high altitudes). We have tested the regulation of CSF pH in healthy men, ponies while awake and dogs while anesthetized during 10 hours to 3 weeks of hypoxia and/or hypocapnia and found consistently that CSF pH is imperfectly regulated and that this regulation depends critically on concomitant changes in the blood, and that the acid-base status of this fluid played no positive role as a mediator of ventilatory acclimatization.